Abstract
Regulation of nuclear factor of activated T cells-c2 (NFATc2) gene expression is not clearly defined. We previously reported reduced NFATc2 protein expression in cord blood T lymphocytes. Here we show that NFATc2 expression in T cells is dependent in part on the presence of IFN-γ during primary stimulation, as blocking of IFN-γ blunted NFATc2 protein and mRNA upregulation. Conversely, addition of exogenous IFN-γ during stimulation resulted in increased expression of NFATc2 in cord blood T lymphocytes. This correlated with rescue of deficient IFN-γ expression by cord blood T cells. Rescue of IFN-γ expression in cord blood T cells was dependent on the presence of antigen-presenting cells, as addition of IFN-γ during stimulation of purified cord blood T cells did not result in an increase of IFN-γ expression, and depletion of monocytes ablated the rescue of IFN-γ expression. Our results point to impaired function in the antigen-presenting cell population of cord blood, playing a role in the hyporesponsiveness of T cells.
Similar content being viewed by others
References
Kurtzberg J, Laughlin M, Graham ML, Smith C, Olson JF, Halperin EC, Ciocci G, Carrier C, Stevens CE, Rubinstein P: Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. N Engl J Med 335:157–166, 1996
Rubinstein P, Carrier C, Scaradavou A, Kurtzberg J, Adamson J, Migliaccio AR, Berkowitz RL, Cabbad M, Dobrila NL, Taylor PE, Rosenfield RE, Stevens CE: Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med 339:1565–1577, 1998
Rocha V, Wagner JJ, Sobocinski K, Klein J, Zhang M, Horowitz M, Gluckman E: Graft-versus-host disease in children who have received a cord blood or bone marrow transplant from an HLA-identical sibling. Eurocord and international bone marrow transplant registry working committee on alternative donor and stem cell sources. N Engl J Med 342:1846–1854, 2000
Laughlin MJ, Barker J, Bambach B, Koc ON, Rizzieri DA, Wagner JE, Gerson SL, Lazarus HM, Cairo M, Stevens CE, Rubinstein P, Kurtzberg J: Hematopoietic engraftment and survival in adult recipients of umbilical cord blood from unrelated donors. N Engl J Med 344:1815–1822, 2001
Chalmers IMH, Janossy G, Contreras M, Navarrete C: Intracellular cytokine profile of cord and adult blood lymphocytes. Blood 92:11–18, 1998
Kadereit S, Mohammad S, Miller R, Daum Woods K, Listrom C, McKinnon K, Alali A, Bos L, Iacobuci M, Sramkoski M,Jacobberger J, Laughlin M: Reduced NFAT1 protein expression in human umbillical cord blood T lymphocytes. Blood 94:3101–3107, 1999
Kadereit S, Kozik M, Junge G, Miller R, Slivka L, Bos L, Daum-Woods K, Sramkoski R, Jacobberger J, Laughlin M: Cyclosporin A effects during primary and secondary activation of human umbilical cord blood T lymphocytes. Exp Hematol 29:903–909, 2001
Ferrara JLM, Krenger W: Graft-versus-host disease: The influence of type 1 and type 2 T cell cytokines. Transfus Med Rev 12:1–17, 1998
Klingebiel T, Schlegel PG: GVHD: Overview on pathophysiology, incidence, clinical and biological features. Bone Marrow Transplant 21:S45-S49, 1998
Pan L, Delmonte JJ, Jalonen CK, Ferrara JL: Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease. Blood 86:4422–4429, 1995
Yang YG: The role of interleukin-12 and interferon-gamma in GVHD and GVL. Cytokines Cell Mol Ther 6:41–46, 2000
Rao A, Luo C, Hogan PG: Transcription factors of the NFAT family: Regulation and Function. Ann Rev Immunol 15:707–747, 1997
Campbell P, Pimm J, Ramassar V, Halloran P: Identification of a calcium-inducible, cyclosporine sensitive element in the IFN-gamma promoter that is a potential NFAT binding site. Transplantation 61:933–939, 1996
Feske S, Muller JM, Graf D, Kroczek RA, Drager R, Niemeyer C, Baeuerle PA, Peter HH, Schlesier M: Severe combined immunodeficiency due to defective binding of the nuclear factor of activated T cells in T lymphocytes of two male siblings. Eur J Immunol 26:2119–2126, 1996
Sica A, Dorman L, Viggiano V, Cippitelli M, Ghosh P, Rice N, Young HA: Interaction of NF-kappaB and NFAT with the interferon-gamma promoter. J Biol Chem 272:30412–30420, 1997
Sweetser M, Hoey T, Sun Y, Weaver W, Price G, Wilson C: The roles of nuclear factor of activated T cells and Ying-Yang 1 in activation-induced expression of the interferon-γ promoter in T cells J Biol Chem 273:34775–34783, 1998
Kiani A, Roa A, Aramburu J: Manipulating immune responses with immunosppressive agents that target NFAT. Immunity 12:359–372, 2000
Hodge MR, Ranger AM, de la Brousse FC, Hoey T, Grusby MJ, Glimcher LH: Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice. Immunity 4:397–405, 1996
Kiani A, Garcia-Cozar FJ, IH, Laforsch S, Aebischer T, Ehninger G, Rao A: Regulation of interferon-gamma gene expression by nuclear factor of activated T cells. Blood 98:1480–1488, 2001
McCaffrey PG, Luo C, Kerppola TK, Jain J, Badalian TM, Ho AM, Burgeon E, Lane WS, Lambert JN, Curran T, Verdine GL, Rao A, Hogan PG: Isolation of the cyclosporin-sensitive T cell transcription factor NFATp. Science 262:750–754, 1993
Lyakh L, Ghosh P, Rice NR: Expression of NFAT-family proteins in normal human T cells. Mol Cell Biol 17:2475–2484, 1997
Crabtree G, Olson E: NFAT signaling: Choreographing the social lives of cells. Cell 109:S67-S79, 2002
Northrop JP, Ho SN, Chen L, Thomas DJ, Timmerman LA, Nolan GP, Admon A, Crabtree GR: NF-AT components define a family of transcription factors targeted in T-cell activation. Nature 369:497–502, 1994
Diehl S, Chow C, Weiss L, Palmetshofer A, Twardzik T, Rounds L, Serfling E, Davis R, Anguita J, Rincon M: Induction of NFATc2 expression by interleukin 6 promotes T helper type 2 differentiation. J Exp Med 196:39–49, 2002
Cron R, Bort S, Wang Y, Brunvand M, Lewis D: T cell priming enhances IL-4 gene expression by increasing nuclear factor of activated T cells. J Immunol 162:860–870, 1999
Miller RE, Fayen JD, Mohammad SF, Stein K, Kadereit S, Daum Woods K, Sramkoski RM, Jacobberger JW, Templeton D, Shurin SB, Laughlin MJ: Reduced CTLA-4 protein and messenger RNA expression in umbilical cord blood T lymphocytes. Exp Hematol 30:738–744, 2002
Helms T, Boehm BO, Asaad RJ, Trezza RP, Lehmann PV, Tary-Lehmann M: Direct visualization of cytokine-producing recall antigen-specific CD4 memory T cells in healthy individuals and HIV patients. J Immunol 164:3723–3732, 2000
Cleveland WS: Robust locally weighted regression and smoothing scatterplots. J Am Stat Assoc 74:829–836, 1979
Verbeke G, Molenberghs G, (eds): Linear Mixed Models in Practice: A SAS-Oriented Approach. New York, Springer, 1997
Quesniaux V: Immunosuppressants: Tools to investigate the physiological role of cytokines. Bioessays 15:731–739, 1993
Forsthuber T, Yip HC, Lehmann PV: Induction of TH1 and TH2 immunity in neonatal mice. Science 271:1728–1730, 1996
Ridge JP, Fuchs EJ, Matzinger P: Neonatal tolerance revisited: Turning on newborn T cells with dendritic cells. Science 271:1723–1726, 1996
Krampera M, Tavecchia L, Benedetti F, Nadali G, Pizzolo G: Intracellular cytokine profile of cord blood T-, and NK-cells and monocytes. Haematologica 85:675–679, 2000
Liu E, Tu W, HKL, Lau YL: Changes of CD14 and CD1a expression in response to IL-4 and granulocyte-macrophage colony-stimulating factor are different in cord blood and adult blood monocytes. Pediatr Res 50:184–189, 2001
Varis I, Deneys V, Mazzon A, De Bruyere M, Cornu G, Brichard B: Expression of HLA-DR, CAM and costimulatory molecules on cord blood monocytes. Eur J Haematol 66:107–114, 2001
Sato K, Nagayama H, Takahashi TA: Aberrant CD3-and CD28-mediated signaling events in cord blood T cells are associated with dysfunctional regulation of Fas ligand-mediated cytotoxicity. J Immunol 162:4464–4471, 1999
Dinter A, Berger EG: Golgi-disturbing agents. Histochem Cell Biol 109:571–590, 1998
Gallucci S, Matzinger P: Danger signals: SOS to the immune system. Curr Opin Immunol 13:114–119, 2001
Matzinger P: An innate sense of danger. Semin Immunol 10:399–415, 1998
Ohteki T, Fukao T, Suzue K, Maki C, Ito M, Nakamura M,Koyasu S: Interleukin 12-dependent interferon gamma production by CD8alpha+ lymphoid dendritic cells. J Exp Med 189:1981–1986, 1999
Hochrein H, Shortman K, Vremec D, Scott B, Hertzog P, O'Keeffe M: Differential production of IL-12, IFN-alpha, and IFN-gamma by mouse dendritic cell subsets. J Immunol 166:5448–5455, 2001
Puddu P, Fantuzzi L, Borghi P, Varano B, Rainaldi G, Guillemard E, Malorni W, Nicaise P, Wolf SF, Belardelli F, Gessani S: IL-12 induces IFN-gamma expression and secretion in mouse peritoneal macrophages. J Immunol 159:3490–3497, 1997
Chensue SW, Ruth JH, Warmington K, Lincoln P, Kunkel SL: In vivo regulation of macrophage IL-12 production during type 1 and type 2 cytokine-mediated granuloma formation. J Immunol 155:3546–3551, 1995
O'Garra A: Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8:275–283, 1998
Lee SM, Suen Y, Chang LVB, Qian J, Indes J, Knoppel E, van de Ven C, Cairo MS: Decreased interleukin-12 (IL-12) from activated cord versus adult peripheral blood mononuclear cells and upregulation of interferon-gamma, natural killer, and lymphokine-activated killer activity by IL-12 in cord blood mononuclear cells. Blood 88:945–954, 1996
Hamza NS, Lisgaris MV, Yadavalli GK, Fu P, Lazarus HM, Koc ON, Salata RA, Laughlin MJ: Infectious complications after unrelated HLA-mismatched allogeneic umbilical cord blood transplantation (UCBT) in adults. Blood 98 204a, 2001
Dorman SE, Holland SM: Interferon-gamma and interleukin-12 pathway defects and human disease. Cytokine Growth Factor Rev 11:321–333, 2000
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kadereit, S., Junge, G.R., Kleen, T. et al. Deficient IFN-γ Expression in Umbilical Cord Blood (UCB) T Cells Can Be Rescued by IFN-γ-Mediated Increase in NFATc2 Expression. J Clin Immunol 23, 485–497 (2003). https://doi.org/10.1023/B:JOCI.0000010425.30967.0f
Issue Date:
DOI: https://doi.org/10.1023/B:JOCI.0000010425.30967.0f